Abstract
Putrescine and spermidine depletion produced by α-difluoromethylornithine, an irreversible inhibitor of omithine decarboxylase (EC 4.1.1.17) greatly enhances the uptake of the anti-cancer drug methylglyoxal bis(guanylhydrazone) by cultured Ehrlich ascites carcinoma cells. The drug was also more effectively retained in the cells previously exposed to the inhibitor of ornithine decarboxylase. When untreated Ehrlich ascites carcinoma cells were shortly exposed to methylglyoxal bis(guanylhydrazone) and then transferred into drug-free medium, they rapidly reinitiated growth, while polyamine-deprived cells were irreversibly damaged upon similar exposure to the drug. Tumor cells with greatly reduced intracellular pools of putrescine and spermidine so effectively concentrated methylglyoxal bis(guanylhydrazone) that the drug largely disappeared from the medium resulting in a formation of concentration gradient of more than 5000-fold across the cell membrane. The tumor cells tolerated high intracellular concentrations (6-9 mM) of methylglyoxal bis(guanylhydrazone) for not more than 24 h whereafter they simply disintegrated and excreted the drug back into the medium. The final destruction of the polyaminedepleted cells in response to methylglyoxal bis(guanylhydrazone) was preceded by profound inhibition of protein synthesis, which occurred before any disturbances in thymidine incorporation were obvious. The inhibition of protein synthesis by methylglyoxal bis(guanylhydrazone) was more pronounced in cells previously exposed to difluoromethylornithine than in cells with normal intracellular polyamine pools. The extent of polyamine depletion produced by difluoromethylornithine and the rate of the uptake of methylglyoxal bis(guanylhydrazone) were positively correlated to the growth rate of the tumor cells, i.e. cells dividing slowly were more resistant towards the action of difluoromethylornithine, as regards the development of intracellular polyamine depletion, and they also accumulated methylglyoxal bis(guanylhydrazone) less effectively than did rapidly dividing cells. The rate of methylglyoxal bis(guanylhydrazone) transport was likewise related to the extent of intracellular putrescine and spermidine deprivation: tumor cells with greatly reduced putrescine and spermidine pools concentrated methylglyoxal bis(guanylhydrazone) more rapidly than cells containing only moderately decreased concentrations of the polyamines. Although the uptake of exogenous spermidine by polyamine-deprived tumor cells was initially at least as rapid as that of methylglyoxal bis(guanylhydrazone), the transport of the natural polyamine was automatically halted when the intracellular spermidine pool was brought to a normal level. It thus appears that the uptake of methylglyoxal bis(guanylhydrazone) by the stimulated transport system of polyamines leads to a suicidal accumulation of the drug and to rapid cell death.
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